Farnesylated tetrahydro-naphthalenols as hypolipidemic agents

ABSTRACT

The invention relates to novel farnesylated tetrahydro-naphthalenols, that inhibit HMGR activity which results in a decrease in serum total cholesterol, a decrease in LDL cholesterol levels, and inhibition of LDL oxidation. The farnesylated tetrahydro-naphthalenols of the present invention are thus useful for cholesterol/lipid lowering in cases of hypercholesterolemia, hyperlipidemia, and atherosclerosis.

The application is a divisional application of parent application Ser.No. 09/749778, filed on Aug. 26, 1991, and now U.S. Pat. No. 5,204,393.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to new farnesylatedtetrahydro-naphthalenols, which are useful for cholesterol/lipidlowering in cases of hypercholesterolemia, hyperlipidemia, andatherosclerosis. Also provided are pharmaceutical compositions and amethod of use employing those compositions.

2 Description of the Prior Art

It is generally recognized that high blood cholesterol levels are asignificant risk factor in cardiovascular disease. Studies havedemonstrated that with very few exceptions, populations which consumelarge quantities of saturated fat and cholesterol have relatively highconcentrations of serum cholesterol and high mortality rate fromcoronary heart disease. (The Expert Panel "Report of the NationalCholesterol Education Program Expert Panel on Detection, Evaluation, andthe Treatment of High Blood Cholesterol in Adults," Arch. Intern. Med.148, 36-39, (1988)).

It has been established that 3-hydroxy-3-methylglutaryl coenzyme Areductase (HMGR) is the first rate limiting enzyme in the biosyntheticpathway for cholesterol, that inhibition of HMGR activity results in adecrease in serum total cholesterol and LDL cholesterol levels, and thata decrease in serum LDL-cholesterol levels is reflected in a reductionof plasma level of apolipoprotein B. (Brown, et al, J. Lipid Res, 21:505-517 (1980)).

Tocotrienols have been shown to suppress HMGR resulting in theinhibition of cholesterol biosynthesis and a subsequent drop in LDLcholesterol, apolipoprotein B, thromboxane B₂, platelet factor 4 andglucose levels. (Wright, et al, A Symposium On Drugs Affecting LipidMetabolism, Houston, Tex. (Nov. 1989)). In J. Biol. Chem, 261:10544-10550, (1986), Qureshi, et al. indicated that thehypocholesterolemic effects of alpha-tocotrienol is brought about by thesuppression of HMGR as measured by hepatic HMGR activity. (Qureshi, etal. J. Biol. Chem, 261: 10544-10550, (1986)). Wright et al, supra,showed that tocotrienol-rich fraction (TRF) fed to hypercholesterolemicswine resulted in a dramatic decrease in serum total cholesterol and LDL-cholesterol levels. Qureshi, et al. showed that gamma anddelta-tocotrienols suppress HMGR activity. (Qureshi, et al. Suppressionof Cholesterolgenesis in Hypercholesterolemic Humans by Tocotrienols ofBarley and Palm Oils, presented at the Antioxidant and DegenerativeDiseases Conference, Berkeley, Calif., (Jan. 1990)). U.S. Pat. No.4,603,142 to Qureshi et al., (1986) discloses the use ofalpha-tocotrienol for the lowering of lipids.

The tocotrienols are structurally related to the tocopherols (vitamin E)and differ only by possessing unsaturation in the isoprenoid side chain.Like the tocopherols, the tocotrienols have antioxidative activity,(Yamaoka, et al, Yukaoaku, 34: 120-122 (1985)). Active oxygen speciesare known to play pivotal roles in the genesis of atheroscleroticplaques, thrombotic episodes, ischemic damage, cancer, aging, dementia,and inflammatory conditions. (Sies, H., Oxidative Stress; AcademicPress, N. Y. , (1985); Santrucek, M., Krepelka, J., Drugs of the Future.13: 973-996 (1988)). Of particular interests are the potentialprotective effects of antioxidants on lipoproteins, since oxidized LDLis thought to be atherogenic. (Buckley, M., Goa, K. L., Price, A. H.,Brogden, R. N., Drugs, 37: 761-800 (1989); Gwynne, J. T., Schwartz, C.J., Am. J. Cardiology, 62: 1B-77B (1988)). The antioxidative activity ofthe tocotrienols may be of value in conjunction with their hypolipidemicproperties.

A possible liability with the tocotrienols is metabolism of the highlyelectron-rich benzopyran nucleus. This could lead to oxidative openingof the pyran ring, additional ring hyroxylation and finally excretionvia bioconjugation reactions. Our objective was to find analoguespossessing greater metabolic stablility. The carba-tocotrienol analogswere found to exhibit enhanced lipid lowering activity relative to thetocotrienols as measured in vivo.

The present invention describes the synthesis and preliminary biologicalevaluation of new farnesylated tetrahydro-naphthalenols analogs.

SUMMARY OF THE INVENTION

The present invention provides farnesylated tetrahydro-naphthalenolswhich are useful for cholesterol/lipid lowering in cases ofhypercholesteremia, hyperlipidemia and atherosclerosis.

Also provided are prodrugs of the compounds of the present invention.

In an embodiment, the present invention provides a pharmaceuticalcomposition which comprises at least one compound of the presentinvention and a non-toxic pharmaceutically acceptable carrier.

In another embodiment, the present invention provides a method oftreating hypercholesteremia, hyperlipidemia and thromboembolic disordersin birds and mammals, including humans, which consists of administeringat least one compound of the present invention to a host in need of suchtreatment.

In yet another embodiment, the present invention provides a method ofinhibiting LDL oxidation in birds and mammals, including humans, whichconsists of administering at least one compound of the present inventionto a bird or mammal in need of such treatment.

In a further embodiment, the present invention provides a method ofmaking the compounds of the present invention.

These and other advantages and objects of the invention will be apparentto those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides tetrahydronaphthalenols of the Formula(I) ##STR1## Wherein

R₁ represents hydrogen, C₁ -C₁₀ lower alkyl, halogen, or OMe;

R₂ represents hydrogen, C₁ -C₁₀ lower alkyl; and

n is 1-3, preferably 3.

The present invention also provides prodrugs of the compounds of FormulaI which prodrugs have the general formula II ##STR2## wherein

R₃ is a physiologically hydrolyzable ester, preferably an ester ofphenol such as acetate, nicotinate or succinate; and R₁, R₂, and n areas described in Formula I.

Due to the carbon-carbon double bond at the 3'-position, the compoundsof Formulas I and II exist as geometric isomers having either the E- orZ- configuration, and the invention includes both isomers and mixturesthereof. The R-isomer, the S-isomer and the racemic mixture (at the C-2position) are also included within the scope of the compounds ofFormulas I and II.

Also included within the scope of the present invention are thepharmaceutically acceptable acid addition salts, the metal salts and thesolvates of the compounds of Formulas I and II which may exist invarious tautomeric forms.

The term "C₁ -C₁₀ lower alkyl" as used herein and in the claims (unlessthe context indicates otherwise) mean branched or straight chain alkylgroups having 1 to 10 carbon atoms such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, etc., preferably one atom. The term"halogen" as used herein and in the claims (unless otherwise specifiedin the particular instance) is intended to include chloride, bromide,fluoride, and iodide.

The term "prodrug" as used herein and in the claims (unless the contextindicates otherwise) denotes an analog of an active drug which isconverted after administration back to the active drug. Moreparticularly, it refers to analogs of tetrahydro naphthanlenols whichare capable of undergoing hydrolysis of the ester moiety or oxidativecleavage of the ester moiety so as to release active, free drug. Thephysiologically hydrolyzable esters serve as prodrugs by beinghydrolyzed in the body to yield the parent drug per se.

Synthesis of Farnesylated Naohthalenols

Synthesis of the naphthalenols 7 and 12 is outlined in schemes I and IIand begins with the known tetralone 1 (Kieboom et al. Synthesis, 476-478(1970)). The known hydroxymethylene derivative 2 [ibid] is prepared in amodified procedure using potassium t-butoxide in toluene at -78° in highyield. Reduction of both carbonyl groups proceeds smoothly using borane(Lau et al., J. Org. Chem., 54: 491 (1989)) to give alcohol 3.Activation of the alcohol required conversion the the reactivetrifluoromethanesulfonate ester. With the triflate 4 in hand,homologation was straightforward using the coupling methodology ofInomata et al., Chem. Letters, 1177 (1986). In this case(E),(E)-farnesyl p-tolysulfone (Greico et al., J. Org. Chem., 39: 2135(1974)) was metalated with n-butyllithium and alkylated with thetriflate 4. Reductive cleavage of the sulfone 5 occursstereospecifically and regiospecifically with Pd(II) and super hydride(Inomata et al., Chem. Letters, 1177 (1986)) to give the farnesylatedcompound 6. Removal of the methyl ether was done using a modification ofthe procedure of Keinan et al., (Pure & Appl. Chem. 60: 89 (1988)) inwhich para-aminothiophenol serves as a nucleophilic reagent fordealkylation. This process occurs cleanly and yields the phenol 7 aindicated in scheme I.

The synthesis of naphthalenol 12 begins with the known tetralone 8(Kieboom et al., Synthesis 476-478 (1970)). This compound undergoessmooth demethylation with pyridine hydrochloride at 220° to give theknown phenol 9 (Buchta et al., Ann. 576: 7-19 (1952)). The phenol wasprotected as its t-butyldimethylsilyl ether 10 and was metalated usinglithium diisopropyl amide. The enolate was coupled with homofarnesyliodide to give the ketone 11 in modest yield. Removal of the ketone tothe methylene oxidation state was done stepwise. Treatment of the ketone11 with lithium aluminum hydride gave an excellent yield of theintermediate alcohols. Reductive cleavage of the benzylic alcohols usinglithium metal in ammonia, required activation by acetylation [failure todo this resulted in reduction of the aromatic ring]. This two stepreduction procedure provided the naphthalenol 12 in good yield as shownin scheme II.

Biological Data

The biological activity of the compounds of Formula I may bedemonstrated in the following biological tests.

β- Hydroxy-β-Methylglutaryl Coenzyme A Reductase (HMGR) activity in theliver of drug dosed chickens.

Serum cholesterol, triglycerides, low density and high densityliproprotein cholesterol as determined in drug treated birds.

Inhibition of LDL oxidation as measured by conjugated diene formation.

Ex Vivo HMGR Suppression and In Vivo Biological Evaluation inNormocholesterolemic Chickens

Newborn male chicks (8 for each group) were raised on a standardcorn-soybean based control diet for two weeks and then switched toeither control or experimental diets for four weeks. Drug treatmentconsisted of the addition of test compounds to the corn-soybean-baseddiet at a concentration of 50 ppm. At the end of the feeding period, allthe birds were fasted (36 hours) and refed (48 hours) to inducecholesterolgenic enzymes prior to sacrifice. The specific activity ofHMGR, total serum cholesterol levels, LDL cholesterol and HDLcholesterol pools were determined using previously described methods(Qureshi et al., J. Biol. Chem., 261, 10544 (1986)) (Table 1).

                  TABLE 1                                                         ______________________________________                                        Effects of test compound and tocotrienol on Lipid                             Metabolism in 6-week old male chickens                                                Total      LDL       HDL                                              Compound                                                                              Cholesterol                                                                              Cholesterol                                                                             Cholesterol                                                                            HMGR                                    ______________________________________                                        Control 183.0 ± 4.5                                                                           62.7 ± 2.5                                                                           99.9 ± 1.9                                                                          33.8                                    No. 12  125.5 ± 3.0                                                                           28.4 ± 1.3                                                                           85.3 ± 1.3                                                                          14.6                                    Tocotrienol                                                                           149.8 ± 4.5                                                                           42.8 ± 2.8                                                                           91.7 ± 1.0                                                                          13.6                                    ______________________________________                                         ##STR3##                                                                      ##STR4##                                                                 

LDL Antioxidant Assay

Whole rabbit plasma was incubated with either vehicle or drug, and theLDL was isolated by ultracentrifugation. EDTA was removed by dialysisand analysis of co-dependent LDL oxidation was determined by conjugateddiene formation using the protocol established by Esterbauer et al.,(Free Radical Res. Commun. 6(1), 75--75 (1989)). The time of the firstderivative maximum in the kinetic curves, corresponding to the end ofthe lag phase (LR) of the reaction, indicates both the intrinsiceffectiveness of the antioxidant combined with its local concentrationwithin the LDL particles. Compound 12 exhibited a LR of 1.32 vs control.Tocotrienol exhibited a LR of 2.01 vs control. This data indicates thattest compound 12 exhibits LDL antioxidation properties. However, asexpected, compound 12 is less effective in this manner than tocotrienol.Substitution of methylene for oxygen at position 1 would diminishantioxidant capacity.

The results to the above tests demonstrates that the compounds ofFormula I and II inhibit HMGR activity which results in a decrease inserum total cholesterol, a decrease in LDL cholesterol levels, andinhibition of LDL oxidation in a manner significantly more efficientthan tocotrienol.

Thus, the compounds of Formulas I and II may be readily administered, totreat hypercholesterolemia, hyperlipidemia, and atherosclerosis, and toinhibit LDL oxidation in avian and mammalian systems in need of suchtreatment. For this purpose, the drug may be administered byconventional routes including, but not limited to, the alimentary canalin the form of oral doses, by injection in sterile parenteralpreparations on nasally.

In yet another aspect, the present invention provides a pharmaceuticalcomposition which comprises a compounds of Formulas I and II and anon-toxic pharmaceutically acceptable carrier. These carriers can besolid or liquid such as cornstarch, lactose, sucrose, olive oil orsesame oil. If a solid carrier is used, the dosage forms may be tablets,capsules, powders, troches or lozenges. If the liquid form is used, softgelatin capsules, syrup or liquid suspensions, emulsions, or solutionsin convenient dosage forms may be used. The composition may be made upof any pharmaceutical form appropriate for the desired route ofadministration. Examples of such compositions include solid compositionsfor oral administration such as tablets, capsules, pills, powders andgranules, liquid compositions for oral administration such as solutions,suspensions, syrups or elixirs and preparations for parenteraladministration such as sterile solutions, suspensions or emulsions. Theymay also be manufactured in the form of sterile solid compositions whichcan be dissolved in sterile water, physiologically saline or some othersterile injectable medium immediately before use.

The dosage ranges will commonly range from about 50 mg to about 200 mg.Optimal dosages and regimes for a given host can be readily ascertainedby those skilled in the art. It will, of course, be appreciated that theactual dose used will vary according to the particular compositionformulated, the particular compound used, the disease being treated.Many factors that modify the action of the drug will be taken intoaccount including age, weight, sex, diet, time of administration, routeof administration, rate of excretion, condition of the patient, drugcombinations, reaction sensitivities and severity of the disease.

All publications cited in this specification are indicative of the levelof skill of those skilled in the art to which this invention pertains.Each publication is individually incorporated herein by reference in thelocation where it is cited. ##STR5##

Chemistry Experimental

The following examples are intended for illustrative purpose only andare not to be construed as limiting the invention in sphere or scope.

All temperatures are understood to be in degrees in C when notspecified. Melting points were recorded on a Thomas-Hoover melting pointapparatus and are uncorrected. Boiling points are uncorrected. Infraredspectra were obtained on a Perkin-Elmer Model 1800 FT-IRspectrophotometer. ¹ H-NMR spectra were recorded on a Bruker AM 300spectrometer or a Varian Gemini 300 NMR spectrometer; nuclear magneticresonance (NMR) spectral characteristics refer to chemical shifts (δ)expressed in parts per million (ppm) with tetramethylsilane (TMS) as aninternal standard. The relative area reported for the various shifts inthe proton NMR spectral data corresponds to the number of hydrogen atomsof a particular functional type in the molecule. The nature of theshifts as to multiplicity is reported as broad singlets (br s), singlets(s), multiplet (m), doublet (d), triplet (t), or quartet (q). Massspectra were measured on a Finnegan 4500 spectrometer (low resolution).

Thin-layer chromatography was performed on silica gel 60 F-254 platespurchased from E. Merck and company (visualization with iodine orphosphomolybdic acid); flash chromatography was performed on fine silica(EM Sciences, 230-240 mesh). All reactions were run under dry nitrogenunless otherwise indicated. Dry solvents were purchased from Aldrich,Milwaukee, Wis. in sure/seal bottles and transferred by syringe undernitrogen. Most commercially available starting materials did not requirefurther purification.

EXAMPLE 1 2-Hydroxymethylene-6-Methoxy-1-Tetralone (2)

A mixture of 6-methoxy-1-tetralone (1) (20 g, 0.113 mole) and ethylformate (16.82 g, 0.23 mole) were dissolved in about 250 mL of toluene.The solution was cooled to about -78° C. under nitrogen and mechanicallystirred while potassium t-butoxide (25.5 g, 0.23 mole) was added inportions giving rise to a reddish colored solution. The mixture wasslowly warmed to about -5° over a period of about one hour at which timeTLC analysis (1:1 EtOAc:Hexanes) indicated a complete conversion to theless polar product. The reaction mixture was quenched with about 10% HCland extracted with ether. The ether extracts were dried (brine, MgSO₄)and concentrated in vacuo to yield 24.4 g of a dark brown oil. The oilwas purified by distillation in a Kugelrohr oven [bath temp.160°-180°/0.1 mm Hg] to yield the title compound as a yellow oil (22.6g, 0.11 mole, 98% yield) that solidified on standing [mp 66°-68°, (Lit.Kieboom et al., Synthesis, 476-478, (1970)), mp 68-69°].

EXAMPLE 2 1,2,3,4-Tetrahydro-6-Methoxy-2-Naohthalenemethanol (3)

2-Hydroxymethylene-6-methoxy-1-tetralone (2) (4.81 g, 0.024 mole) andborane:t-butylamine complex (10.25 g, 0.12 mole) were dissolved in about250 mL of methylene chloride and the solution was cooled to about -78°.Boron trifluoride etherate (14.5 mL, 0.12 mole) was added dropwise andthe mixture was stirred for about 1 hour then warmed to about 23° andstirred for an additional 2 hours. The reaction mixture was quenchedwith about 1 N HCl and extracted with methylene chloride. The methylenechloride extracts were dried (MgSO₄) and concentrated in vacuo. Thecrude oil was purified by flash chromatography [gradient 3:1 to 1:2Hexanes:Ether] to yield the title compound as a light yellow oil (3.41g, 0.018 mole, 75% yield): IR (Film) 3362, 2996, 2918, 1610, 1504, 1464,1264, 1234, 1040 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.40 (m, 1H) , 1.47 (s, 1H),1.95 (m, 2H), 1.39,1.45 (d of d, J=10.6,16.1 Hz, 1H), 2.81 (m, 2H), 3.62(d, J=6.3 Hz, 2H), 3.77 (s, 3H), 6.62 (d, J=2.6 Hz, 1H), 6.68 (d of d,J=8.4,2.6 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H); MS m/e 193 (MH³⁰).

Anal. Calcd. for C₁₂ H₁₆ O₂ :

C, 74.97; H, 8.39.

Found: 74.70; H, 8.37.

EXAMPLE 3 1,2,3,4-Tetrahydro-6-Methoxy-2-NaohthalenemethanolTrifluoromethanesulfonate (4)

1,2,3,4-Tetrahydro-6-methoxy-2-naphthalenemethanol (2.0 g, 10.42 mmole)and triethylamine (2.2 mL, 15.6 mmole) were dissolved in about 20 mL ofmethylene chloride and the solution was cooled to about -78° undernitrogen. Triflic anhydride (2.27 mL, 13.54 mmole) was added dropwisethe stirred mixture at about -78°. After the addition, the mixture waswarmed to about -5°, at which time TLC [2:1 hexanes:EtOAc] indicatedcomplete conversion to the less polar triflate ester. The reactionmixture was quenched with about 1 N HCl and extracted with methylenechloride. The methylene chloride extracts were dried (MgSO₄) andconcentrated in vacuo. The crude oil was purified by flashchromatography [5:1 Hexanes:Ether] to yield the title compound as alight yellow oil that solidified on standing [mp 52°-54° ](3.15 g, 9.72mmole, 93% yield). The triflate ester was somewhat unstable; a smallsample turned black after several hours at about 23°. The bulk wasstored at about -20° and was used without delay in the next step: ¹ HNMR (CDCl₃) δ 1.55 (m, 1H), 2.03 (m, 1H), 2.30 (m, 1H), 2.49,2.55 (d ofd, J=10,16 Hz, 1H), 2.85 (m, 3H), 3.77 (s, 3H), 4.50 (d, J=6 Hz, 2H),6.64 (d, J=2 Hz, 1H), 6.71(d of d, J=8,2 Hz, 1H), 7.01(d, J=8 Hz, 1H).

EXAMPLE 46-Methoxy-2-[2-[(4-Methylohenyl)sulfonl]-4,8,12-Trimethyl-3(E),7(E),11-tridecatrieny]1,2,3,4-Tetrahydronaohthalene (5 )

n-Butyllithium (7.3 mL, 1.6 M, 11.66 mmole) was added dropwise to asolution of all trans farnesyl p-tolysulfone (3.85 g, 10.69 mmole) inTHF (30 mL), under nitrogen, at about -78°. The orange-colored anion wasstirred for about 45 minutes at about -78° then HMPA (5 mL) was added,followed by 1,2,3,4-tetrahydro-6-methoxy-2-naphthalenemethanoltrifluoro-methanesulfonate (3.15 g, 9.72 mmole) as a THF solution (3mL). The mixture was slowly warmed to about 23° over a period of about 2hours at which time TLC [2:1 hexanes:EtOAc] indicated completeconsumption of the triflate, comensurate with the formation of a spotco-eluting with farnesyl p-tolysulfone. The reaction mixture was pouredinto water and extracted with ether. The ether extracts were dried(brine, MgSO₄) and concentrated in vacuo to give a light oil.Purification of the crude material by flash chromatography [gradient 6:1to 5:1 Hexanes:EtzO] yielded the title compound as a clear viscous oil(5.62 g, >100%) which contained about 10% farnesyl p-tolysulfone asindicated by PMR. An analytical sample was obtained by crystallizationfrom methanol which yielded white crystals mp 64°-66°: IR (Film) 3444,2964, 2916, 1610, 1504, 1450, 1298, 1146 cm^(-1;) ; ¹ H NMR (CDCl₃) δ1.25 (d, J=1.2 Hz, 2H), 1.20-1.34 (m, 2H), 1.54 (s, 3H), 1.55 (s, 3H),1.57 (s, 3H), 1.66 (s, 3H), 1.7-2.0(m, 9H), 2.37-2.47 (m, 1H), 2.46 (s,3H), 2.60-2.80 (m, 3H), 3.75 (s, 3H), 3.90 (d of t, J=3.0,10.9 Hz, 1H),4.92-5.0 (m, 3H), 6.57 (d, J=2.6 Hz, 1H), 6.65 (d of d, J=8.4,2.6 Hz,1H), 6.92 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz,2H) ; MS m/e 379 (M(-C₇ H₇ S₁ O₂)⁺).

Anal. Calcd. for C₃₄ H₄₆ O₃ S₁ :

C, 76.36; H, 8.67.

Found: C, 76.63; H, 8.82.

EXAMPLE 56-Methoxy-2-(4,8,12-Trimethyl-3(E),7(E),11-tridecatrienyl]-1,2,3,4-Tetrahvdronahthalene(6)

6-Methoxy-2-[2-[(4-methylphenyl)sulfonyl]-4,8,12-trimethyl-3(E),7(E),11-tridecatrienyl]-1,2,3,4-tetrahydronaphthalene(2.5 g, 4.68 mmole) was dissolved in about 20 mL of THF. Palladiumchloride:diphenylphosphinylbutane (141 mg, 0.23 mmole) was added and theheterogeneous mixture was cooled to about -5° under nitrogen. Lithiumtriethylborohydride (9.4 mL, 1.0 M, 9.4 mmole) was added dropwise givingrise to a brown homogeneous solution. The mixture was stirred for about12 hours at about -3° then poured into water and extracted with ether.The ether extracts were dried (brine, MgSO₄) and concentrated in vacuoto give a light oil. Purification of the crude material by flashchromatography [gradient hexanes to 20:1 Hexanes:Et₂ O] yielded thetitle compound as a clear oil (1.03 g, 2.71 mmole, 58%). A sample wasdistilled in a Kugelrohr oven [bath 160°-180°/0.1 mm] for analysis: IR(Film) 2916, 2852, 1612, 1504, 1452, 1266, 1042 cm⁻¹ ; ¹ H NMR (CDCl₃) δ1.37 (m, 2H), 1.50-1.70 (m, 3H), 1.58 (s, 6H), 1.62 (s, 3H), 1.66 (s,3H), 1.88-2.10 (m, 10H), 2.30,2.35 (d of d, J=10.6, 16.4 Hz, 1H), 2.77(m, 3H), 3.76 (s, 3H), 5.10 (m, 3H), 6.60 (d, J=2.6 Hz, 1H), 6.66 (d ofd, J=8.4,2.6 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H); MS m/e 381 (MH⁺).

Anal. Calcd. for C₂₇ H₄₀ O₁ :

C, 85.20; H, 10.59.

Found: C, 85.27; H, 10.75.

EXAMPLE 6

1,2,3,4-Tetrahydro-2-(4,8,12-Trimethyl-3(E),7(E),11-tridecatrienyl)-6-Nahthalenol(7)

6-Methoxy-2-(4,8,12-trimethyl-3(E),7(E),11-tridecatrienyl]-1,2,3,4-tetrahydronaphthalene(957 mg, 2.51 mmole), p-aminothiophenol (630 mg, 5.03 mmole), and cesiumcarbonate (410 mg, 1.26 mmole) were suspended in about 3 mL of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone [DMPU]. The flask waspurged well with nitrogen and the mixture was heated to about 200° forabout 3.5 hours. The honey colored mixture was poured into 1 N HCl andextracted with ether. The ether extracts were dried (brine, MgSO₄) andconcentrated in vacuo. Purification of the crude material by flashchromatography [gradient 20:1→10:1 Hexanes:Et₂ O] yielded the titlecompound as a clear oil (800 mg, 2.19 mmole, 87%). A sample wasdistilled in a Kugelrohr oven [bath 180°-200°/0.1 mm] for analysis: IR(Film) 3346, 2916, 2852, 1612, 1502, 1450, 1230, 1150 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 1.37 (m, 2H), 1.50-1.70 (m, 3H), 1.58 (s, 6H), 1.62 (s, 3H),1.66 (s, 3H), 1.88-2.10 (m, 1OH), 2.30,2.35 d of d, J=10.6,16.4 Hz, 1H),2.77 (m, 3H), 4.45 (s, 1H), 5.10 (m, 3H), 6.53 (d, J=2.6 Hz, 1H), 6.57(d of d, J=8.4,2.6 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H); MS m/e 367 (MH³⁰).

Anal. Calcd. for C₂₆ H₃₈ O₁ ;

C, 85.19 H, 10.45.

Found: C, 84.98; H, 10.64.

EXAMPLE 7 2-Methyl-6-Methoxy-1-Tetralone (8)

A: 2-Benzoyloxymethylene-6-Methoxy-1-Tetralone

Benzoyl chloride (11.4 ml, 0.1 mole) was added to a stirred solution of2-hydroxymethylene-6-methoxy-1-tetralone 2 (10 g, 0.05 mole) in about 60mL of pyridine at about 0°. After the addition was complete, the mixturewas stirred at about 23° for about 2 hours then poured into water. Thesolid was filtered and washed with water. The pure product was obtainedby recrystallization from methanol to yield2-benzoyloxymethylene-6-methoxy-1-Tetralone (12.1 g, 0.04 mole, 80%yield), mp 128.5°-129.5°, [Lit. Kieboom et al., Synthesis, 476-478,(1970), mp 130°-130.5°].

B: 2-Methyl-6-Methoxy-1-Tetralone

2-Benzoyloxymethylene-6-methoxy-1-tetralone (4.6 g, 0.015 mole) washydrogenated over platinum oxide (160 mg) in isopropyl alcohol (150 mL)at 55 psi in a Parr hydrogenation apparatus. After about 90 minuteshydrogen uptake ceased and the reaction was stopped. The catalyst wasremoved by filtration and the solvents were removed in vacuo. The titlecompound (2.0 g, 0.011 mole, 70% yield) was obtained after purificationby flash chromatography [gradient 10:1 to 5:1 EtOAc:Hexanes].

EXAMPLE 8 2-Methyl-6-Hydroxy-1-Tetralone (9)

2-Methyl-6-Methoxy-1-Tetralone (19 g, 0.1 mole) and pyridinehydrochloride (53.1 g, 0.46 mole) were heated neet, under a nitrogensweep at about 220° for about 2 hours. The melt was cooled, acidifiedwith 1N HCl and dissolved in ethyl acetate. The organic layers weredried (brine, MgSO₄) and concentrated in vacuo. Purification by flashchromatography [gradient 7:1 to 5:1 EtOAc:Hexanes] yielded the titlecompound as a light yellow solid (14.8 g, 0.084 mole, 84% yield), [Lit.Buchta et al., Ann. 576, 7-19 (1952)].

EXAMPLE 9 6-Dimethyl-(1,1-Dimethylethyl)silyloxy-2-Methyl-1-Tetralone(10)

2-Methyl-6-hydroxy-1-tetralone 14.5 g, 0.082 mole), t-butyldimethylsilylchloride (14.9 g, 0.099 mole) and imidazole (14.6 g, 0.21 mole) weredissolved in about 330 mL of DMF. The mixture was allowed to stir atabout 23° for about 12 hours. The reaction mixture was poured into waterand extracted with ether. The ether extracts were dried (brine, MgSO₄)and concentrated in vacuo to give a light brown oil. Purification of thecrude material by flash chromatography [10:1 Hexanes:EtOAc] yielded thetitle compound as a light yellow oil (23.2 g, 0.08 mole, 97% yield): ¹ HNMR (CDCl₃) δ 0.22 (s, 6H), 0.97 (s, 9H), 1.23 (d, J=6.8 Hz, 3H), 1.85(m, 1H), 2.15 (m, 1H), 2.52 (m, 1H), 2.90 (m, 2H), 6.62 (d, J=2.3 Hz,1H), 6.72 (d of d, J=2.3, 8.6 Hz, 1H), 7.94 d, J=8.6 Hz, 1H); MS m/e291(MH⁺).

EXAMPLE 103,4-Dihydro-6-(1,1-Dimethylethyl)silyloxy-2-Methyl-2-(4,8,12-Trimethyl-3(E).7(E),11-tridecatrienyl)-1(2H)-Naphthalenone (11)

Lithium diisopropylamide (24 mL, 1.5 M, 0.036 mole) was added to about25 mL of dry THF under nitrogen at about -78°.6-Dimethyl-(1,1-dimethylethyl)silyloxy-2-methyl-1-tetralone (6.96 g,0.024 mole) was added to the LDA solution as a THF solution (15 mL). Themixture was stirred at about -78° for about 2 hours at which time about5 mL of DMPU followed by homofarnesyl iodide (8.3 g, 0.024 mole) wereadded. The mixture was stirred at about -3° for about 12 hours thenwarmed to about 23° and stirred for an additional 24 hours. The reactionmixture was quenched with about 1 N HCl and extracted with ether. Theether extracts were dried (brine, MgSO₄) and concentrated in vacuo togive a dark brown oil. The oil was purified by flash chromatography[50:1 EtzO:Hexanes] to yield the title compound as a light yellow oil(1.8 g, 0.004 mole, 15% yield): ¹ H NMR (CDCl₃)δ 0.22 (s, 6H), 0.97 (s,9H), 1.18 (s, 3H), 1.45-1.69 (m, 4H), 1.56 (s, 6H), 1.58 (s, 3H), 1.66(s, 3H), 1.85-2.11 (m, 1OH), 2.88 (m, 2H), 5.07 (m, 3H), 6.60 (d, J=2.1Hz, 1H), 6.72 (d of d, J=2.1, 8.6 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H); MSm/e 509 (MH⁺).

EXAMPLE 11 5,6,7,8-Tetrahydro-6-Methyl-6- 4,8,12-Trimethyl-3(E),(7E),11-tridecatrienyl)-2-Naphthalenol (12)

A:2-(1,1-Dimethylethyl)silyloxy-6-Methyl-6-(4,8,12-Trimethyl-3(E),7(E),11-tridecatrienyl)-5,6,7,8-Tetrahydronaphthalene

3,4-Dihydro-6-(1,1-dimethylethyl)silyloxy-2-methyl-2-(4,8,12-trimethyl-3(E),7(E),11-tridecatrienyl)-1(2H)-naphthalenone(1.8 g, 3.5 mmole) was added as an ether solution (5 mL) to a suspensionof lithium aluminum hydride (133 mg, 3.5 mmole) in about 75 mL of etherat about -78°. The mixture was stirred for about 1 hour at about -78°then warmed to about -5° at which time TLC [10:1 Hexanes:Ether]indicated complete conversion to the more polar alcohol. The reactionwas quenched at about -5° with saturated sodium sulfate solution, pouredinto about 1 N HCl and extracted with ether. The ether extracts weredried (brine, MgSO₄) and concentrated in vacuo to give a light brown oilwhich was used directly in the next step.

A mixture of the above alcohol (1.4 g, 2.7 mmole), dimethylaminopyridine(33 mg, 0.27 mmole), triethylamine (416 mg, 4.1 mmole), and aceticanhydride (308 mg, 3.0 mmole) were dissolved in about 15 mL of methylenechloride and stirred at about 23° for about 12 hours at which time TLC[10:1 Hexanes:Ether] indicated complete conversion to the acetate ester.The organic fractions were washed successively with about 1 N HCl andsaturated NaHCO₃ solutions then dried (MgSO₄) and concentrated in vacuoto give a light brown oil (1.5 g): ¹ H NMR (CDCl₃) δ 0.18 (s, 6H), 0.96(s, 9H), 0.87,0.96? (s, 3H) [diastereomeric methyl signals], 1.45-1.69(m, 4H), 1.58 (s, 9H). 1.66 (s, 3H), 1.85-2.11 (m, 10H), 2.03,2.05 (s,3H)[diastereomeric acetoxy signals], 2.67 (m, 2H), 5.07 (m, 3H),5.68,5.70 (s, 1H)[diastereomeric benzylic methine signals] 6.56 (m, 1H),6.60 (m, 1H), 7.09,7.16 (d of d, J=8.6 Hz, 1H) [diastereomeric arylsignals]; MS m/e 493 (M -[C₂ H₃ O₂ ]⁺).

To a 1:1 mixture of ammonia/THF (30 mL) at refIux temperature was addedlithium metal (5.7 mg, 8.1 mmole) followed by the acetate above (1.5 g,2.7 mmole) as a THF solution (3 mL). Solid ammonium chloride (1.6 g,mortar ground) was added to the solution and the cooling bath wasremoved. The reaction mixture was poured into water and extracted withether. The ether extracts were dried (brine, MgSO₄) and concentrated invacuo to give a light oil. Purification of the crude material by flashchromatography [20:1 Hexanes:Et₂ O] yielded 2-(1,1-Dimethylethyl)silyloxy-6-Methyl-6-(4,8,12-Trimethyl-3(E),7(E),11-tridecatrienyl)-5,6,7,8-Tetrahydronaphthalene as a lightoil (1.0 g, 2.0 mmole, 57% overall yield).

B: 5,6,7,8-Tetrahydro-6-Methyl-6-(4,8,12-Trimethyl-3(E),7(E),11-tridecatrienyl)-2-Naphthalenol

2-(1,1-Dimethylethyl)silyloxy-6-methyl-6-(4,8,12-trimethyl-3(E),7(E),11-tridecatrienyl)-5,6,7,8-tetrahydronaphthalene(1.0 g, 2.0 mmole) was dissolved in about 5 mL of ether. The solutionwas cooled to about -5° and tetrabutylammonium fluoride (2.2 mL, 1 M,2.2 mmole) was added. The mixture was allowed to warm to about 23° andstirred for an additional 10 minutes. The reaction mixture was pouredinto water and extracted with ether. The ether extracts were dried(brine, MgSO₄) and concentrated in vacuo to give a light oil.Purification of the crude material by flash chromatography [20:1Hexanes:Et₂ O] yielded the title compound as a clear oil (700 mg, 1.84mmole, 92%): lR (Film) 3344, 2964, 2916, 1612, 1502, 1448, 1218, 1104cm⁻¹ ; ¹ H NMR (CDCl₃) δ 0.93 (s, 3H), 1.20-l.34 (m, 2H), 1.50-1.70 (m,2H), 1.59 (s, 9H), 1.67 (s, 3H), 1.88-2.10 (m, 10H), 2.45 (AB q, J=16.8Hz, 2H), 2.72 (t, J=6.8 Hz, 2H) , 4.46 (s, 1H), 5.10 (m, 3H), 6.56 (s,1H), 6.57 (d, J=8.0 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H); MS m/e 381 (MH⁺).

Anal. Calcd. for C₂₇ H₄₀ O₁ :

C, 85.20; H, 10.59.

Found: C, 84.89; H, 10.81.

We claim:
 1. The compound having the structural formula (II) ##STR6##wherein R₃ is a physiologically hydrolyzable ester;R₁ representshydrogen, C₁ -C₁₀ lower alkyl, halogen, or OMe; R₂ represents hydrogen,C₁ -C₁₀ lower alkyl; and n is 1-3;or pharmaceutically acceptable acidaddition salts, metal salts or solvates thereof.
 2. The compound ofclaim 1 which is the racemic mixture at the C-2 position.
 3. Thecompound of claim 1 which is the R-isomer at the C-2 position.
 4. Thecompound of claim 1 which is the S-isomer at the C-2 position.
 5. Apharmaceutical composition for treating hypercholesterolemia whichcomprises an effective amount of at least one compound of claim 1, orsalt, hydrate or solvate thereof, in combination with a pharmaceuticalacceptable carrier or diluent.
 6. The method of treating hyperlipidemiahypercholesterolemia, and LDL oxidation in a bird of mammal, whichcomprises administering to said bird or mammal a safe and effectiveamount of at least one compound having the Formula (II) ##STR7## whereinR₃ is a physiologically hydrolyzable ester;R₁ represents hydrogen, C₁-C₁₀ lower alkyl, halogen or OMe; R₂ represents hydrogen, C₁ -C₁₀ loweralkyl; and n is 1-3.